Darolutamide 300mg tablets

Abstract Management of non-metastatic castration-resistant prostate cancer (nmCRPC) has undergone a paradigm shift with next-generation androgen receptor inhibitors. However, direct comparative data are not available to inform treatment decisions and/or guideline recommendations. Therefore, we performed network meta-analysis to indirectly compare the efficacy and safety of currently available treatments. Multiple databases were searched for articles published before June 2020. Studies that compared overall and/or metastasis-free and/or prostate-specific antigen (PSA) progression-free survival (OS/MFS/PSA-PFS) and/or adverse events (AEs) in nmCRPC patients were considered eligible. Three studies ( n  = 4117) met our eligibility criteria. Formal network meta-analyses were conducted. For MFS, apalutamide, darolutamide, and enzalutamide were significantly more effective than placebo, and apalutamide emerged as the best option ( P score: 0.8809). Apalutamide [hazard ratio (HR): 0.85, 95% credible interval (CrI): 0.77–0.94] and enzalutamide (HR: 0.86, 95% CrI: 0.78–0.95) were both significantly more effective than darolutamide. For PSA-PFS, all three agents were statistically superior to placebo, and apalutamide emerged as the likely preferred option ( P score: 1.000). Apalutamide (HR: 0.71, 95% CrI: 0.69–0.74) and enzalutamide (HR: 0.76, 95% CrI: 0.74–0.79) were both significantly more effective than darolutamide. For AEs (including all AEs, grade 3 or grade 4 AEs, grade 5 AEs, and discontinuation rates), darolutamide was the likely best option. Apalutamide and enzalutamide appear to be more efficacious agents for therapy of nmCRPC, while darolutamide appears to have the most favorable tolerability profile. These findings may facilitate individualized treatment strategies and inform future direct comparative trials.

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Abstract Background The most recent overall survival (OS) and adverse event (AE) data have not been compared for the three guideline-recommended high-risk non-metastatic castration-resistant prostate cancer (nmCRPC) treatment alternatives. Methods We performed a systematic review and network meta-analysis focusing on OS and AE according to the most recent apalutamide, enzalutamide, and darolutamide reports. We systematically examined and compared apalutamide vs. enzalutamide vs. darolutamide efficacy and toxicity, relative to ADT according to PRISMA. We relied on PubMed search for most recent reports addressing prospective randomized trials with proven predefined OS benefit, relative to ADT: SPARTAN, PROSPER, and ARAMIS. OS represented the primary outcome and AEs represented secondary outcomes. Results Overall, data originated from 4117 observations made within the three trials that were analyzed. Regarding OS benefit relative to ADT, darolutamide ranked first, followed by enzalutamide and apalutamide, in that order. In the subgroup of PSA-doubling time (PSA-DT) ≤ 6 months patients, enzalutamide ranked first, followed by darolutamide and apalutamide in that order. Conversely, in the subgroup of PSA-DT 6–10 months patients, darolutamide ranked first, followed by apalutamide and enzalutamide, in that order. Regarding grade 3+ AEs, darolutamide was most favorable, followed by enzalutamide and apalutamide, in that order. Conclusion The current network meta-analysis suggests the highest OS efficacy and lowest grade 3+ toxicity for darolutamide. However, in the PSA-DT ≤ 6 months subgroup, the highest efficacy was recorded for enzalutamide. It is noteworthy that study design, study population, and follow-up duration represent some of the potentially critical differences that distinguish between the three studies and remained statistically unaccounted for using the network meta-analysis methodology. Those differences should be strongly considered in the interpretation of the current and any network meta-analyses.

Abstract licence: CC BY 4.0

BackgroundDarolutamide is the next-generation androgen receptor inhibitor approved for the treatment of advanced prostate cancer, including non-metastatic castration-resistant prostate cancer (nmCRPC) and metastatic hormone-sensitive prostate cancer (mHSPC). However, the efficacy and safety of darolutamide are nonetheless worthy of further clinical studies. The objective of this meta-analysis was to evaluate the overall survival, metastasis-free survival and various specific adverse events of darolutamide combination therapy in patients with mHSPC or nmCRPC.MethodsThis meta-analysis was performed on PubMed, EMBASE, Web of Science, ClinicalTrials.gov, and the Cochrane Library for English-language articles to collect randomized clinical trials of darolutamide combination therapy in mHSPC and nmCRPC from the start of the database to 15 January 2026. The primary efficacy outcomes were overall survival and metastasis-free survival. Key safety outcomes included the total number of overall adverse events, the total number of grade ≥3 adverse events and serious adverse events, and the occurrence of specific adverse events of interest. The risk of bias was assessed by the Cochrane risk-of-bias tool for randomized trials (RoB 2). Publication bias was assessed by funnel plots.ResultsThere were 8 research articles from 3 randomized clinical trials with 3,483 patients involved in this meta-analysis, including 1,509 nmCRPC patients from the ARAMIS trial, 1974 mHSPC patients from the ARASENS and ARANOTE trials. Combining darolutamide with ADT significantly prolonged overall survival (OS) and metastasis-free survival (MFS) in nmCRPC patients compared with placebo plus ADT. And darolutamide plus ADT with or without docetaxel also showed favorable overall survival in mHSPC patients. Subgroup meta-analyses of OS among mHSPC patients for baseline total PSA (tPSA) values and Gleason scores showed the beneficial efficacy of darolutamide in mHSPC. The addition of darolutamide in ADT and/or docetaxel did not lead to serious adverse events, like heart failure, bone fracture and hypertension, in both nmCRPC and mHSPC patients.ConclusionDarolutamide combination therapy was beneficial to the prognosis and demonstrated a favorable safety profile in patients with advanced prostate cancer.Systematic review registrationIdentifier CRD420251145736.

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BackgroundProstate cancer is the second most common cancer in men. Androgen deprivation therapy (ADT) is the standard treatment, but many patients develop resistance, leading to metastatic castration-resistant prostate cancer (CRPC). Darolutamide, an androgen receptor inhibitor, has shown promise in treating prostate cancer, but its combination with ADT remains under-researched. This study evaluated the safety and efficacy of darolutamide with ADT in patients with hormone-sensitive prostate cancer and CRPC compared to ADT plus placebo.MethodsWe searched electronic databases for randomized controlled trials on darolutamide + ADT in prostate cancer. The primary outcome was overall survival, and secondary outcomes included pain progression, time to subsequent antineoplastic therapy, and adverse events (fatigue, bone fractures, falls, mental disorders, rash, hypertension, and serious events).ResultsFour studies (N = 3,473) were included. Darolutamide + ADT showed no significant difference in overall survival (HR = 0.71, P = 0.28), but CRPC patients had improved survival (HR = 1.08, P = 0.007). The combination reduced pain progression [risk ratio (RR) = 0.81, P = 0.001] and delayed subsequent therapy (RR = 0.46, P P = 0.008) and hypertension (RR = 1.28, P = 0.03) were increased. Other adverse events, such as fatigue, rash, mental disorders, falls, and serious adverse events, showed no significant differences compared to ADT plus placebo.ConclusionDarolutamide + ADT improves outcomes for PC patients but presents safety concerns, including bone fractures and hypertension. Further trials are needed for optimal patient selection and long-term management.

Abstract licence: CC BY-ND

BackgroundNovel hormonal therapies (NHTs) have substantially improved outcomes in prostate cancer across multiple disease states. However, their hepatic safety remains clinically relevant because treatment is often prolonged and may be combined with androgen-deprivation therapy, corticosteroids, or chemotherapy. We performed a systematic review and meta-analysis to quantify the risk of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations associated with NHT-based therapy.MethodsThis study was conducted in accordance with PRISMA guidelines. Randomized controlled trials comparing NHT-containing regimens with control regimens in patients with prostate cancer were eligible if they reported extractable ALT and/or AST adverse-event data. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated for four prespecified outcomes: all-grade ALT elevation, grade ≥ 3 ALT elevation, all-grade AST elevation, and grade ≥ 3 AST elevation.ResultsTen randomized studies reported in 11 publications were included, involving 10,173 participants treated with abiraterone, enzalutamide, darolutamide, or abiraterone plus enzalutamide combination regimens. Compared with controls, NHT-based therapy significantly increased the risk of all-grade ALT elevation (RR 1.49, 95% CI 1.12-2.00; I2 = 82.8%), grade ≥ 3 ALT elevation (RR 5.91, 95% CI 2.86-12.20; I2 = 67.5%), all-grade AST elevation (RR 1.58, 95% CI 1.02-2.45; I2 = 84.5%), and grade ≥ 3 AST elevation (RR 3.32, 95% CI 2.13-5.18; I2 = 0%). Subgroup analyses suggested that the hepatic safety signal was more evident for abiraterone-containing and abiraterone plus enzalutamide combination regimens, whereas estimates for enzalutamide and darolutamide varied across outcomes and should be interpreted cautiously because of the limited number of available comparisons.ConclusionsNHT-based therapy for prostate cancer was associated with an increased risk of hepatic enzyme abnormalities, particularly severe ALT elevation. The hepatic safety signal appeared more evident for abiraterone-containing and combination regimens, whereas drug-specific estimates for enzalutamide and darolutamide remained limited. Because this analysis focused on laboratory-defined ALT and AST elevations, careful liver function monitoring remains warranted during NHT-based therapy, especially in patients receiving abiraterone-containing or prolonged combination regimens.

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Aim: Recent network meta-analyses (NMAs) in metastatic castration-sensitive prostate cancer have not adequately addressed potential treatment effect modifiers and population imbalances, which introduces bias. Although, individual-patient data (IPD) are seldom available across all trials, recent methodological advances allow adjustments using a combination of IPD and aggregate data. Materials & methods: IPD from the ARASENS trial (darolutamide + docetaxel + androgen-deprivation-therapy [ADT]) and aggregate data from a systematic review were analyzed. Two methods were used to adjust for population imbalances: multilevel network meta-regression (ML-NMR) using baseline characteristics, and network meta-interpolation (NMI) using subgroup data. Relative effects were estimated for an ARASENS-like population, with sensitivity analysis in an average trial population. Results: Twelve studies, including ARASENS, were included. All studies reported baseline characteristics for ML-NMR. Sufficient subgroup data for NMI were available in 8/12 studies for overall survival (OS) and 5/12 studies for progression-free survival (PFS). Darolutamide + docetaxel + ADT showed significant benefit over docetaxel + ADT, ADT and standard-nonsteroidal-antiandrogen + ADT in all analyses. ML-NMR showed improved OS for darolutamide + docetaxel + ADT compared with abiraterone + docetaxel + ADT, apalutamide + ADT, enzalutamide + ADT and abiraterone + ADT. ML-NMR also showed improved PFS for darolutamide + docetaxel + ADT compared with apalutamide + ADT and enzalutamide + ADT. Using NMI, darolutamide + docetaxel + ADT demonstrated OS benefit over abiraterone + ADT and PFS benefit relative to abiraterone + ADT and apalutamide + ADT. Findings were consistent in an average population, although ML-NMR did not show significant OS benefit of darolutamide + docetaxel + ADT over apalutamide+ADT. Conclusion: Improved outcomes were observedwith darolutamide+docetaxel+ADT compared with other therapies. By incorporating effect modifiers and addressing population imbalances, we provide clinicians with a more accurate understanding of treatment efficacy for better-informed decision-making.

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BackgroundProstate cancer represents the third leading cause of cancer-related mortality in the male population. Androgen deprivation therapy efficacy has been significantly enhanced by the addition of docetaxel chemotherapy and androgen receptor pathway inhibitors (ARPI), such as abiraterone, enzalutamide, apalutamide, and darolutamide. These agents have demonstrated improvements in both overall survival (OS) and progression-free survival (PFS). Nevertheless, a subset of patients eventually progresses to metastatic castration-resistant prostate cancer (mCRPC). The prostate-specific antigen (PSA) nadir, defined as the lowest PSA level achieved during therapy, has emerged as an early surrogate marker of treatment response and favorable prognosis.ObjectiveWe conducted a meta-analysis to elucidate the prognostic value of the depth of PSA response in patients with metastatic metastatic hormone-sensitive prostate cancer (mHSPC) treated with ARPI or docetaxel.Patients and methodsThis is a reconstructed individual patient data (IPD) meta-analysis, in which prospective and retrospective clinical trials concerning patients with mHSPC who received first-line therapy with an ARPI or docetaxel were included. Prospective or retrospective studies on mHSPC patients with available data on the lowest value of PSA reached were included. IPD from the Kaplan-Meier curves of enrolled studies were obtained with the software IPDfromKM. Primary endpoints of the analysis were overall survival (OS) and progression-free survival (PFS) in patients who reached a PSA nadir ≤ 0.2 versus PSA nadir > 0.2.ResultsA total of 8 reports from 8 studies were included, collecting data from 1638 patients for the OS analysis and 1104 for the PFS analysis. In terms of median PFS (mPFS), the PSA nadir ≤ 0.2 arm had an advantage: mPFS not reached (NR) versus 12.1 months HR 0.19 (95% CI 0.16-0.23, p 0.2: mOS 92.8 months versus 34 months (HR 0.27, 95% CI 0.22-0.33, p ConclusionsThis meta-analysis confirms the prognostic value of PSA nadir in patients with mHSPC treated with docetaxel or ARPIs. Achieving a PSA nadir ≤ 0.2 ng/mL was significantly associated with improved OS and PFS, highlighting its relevance as an early marker of treatment efficacy.

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